PRODUCT MONOGRAPH. Fluconazole Tablets, House Standard 50 mg and 100 mg ANTIFUNGAL AGENT

Transcription

1 PRODUCT MONOGRAPH Pr pms-fluconazole Fluconazole Tablets, House Standard 50 mg and 100 mg ANTIFUNGAL AGENT PHARMASCIENCE INC Royalmount Ave., Suite 100 Montréal, Québec H4P 2T4 Date of Revision: July 29, Submission Control No.: pms-fluconazole Product Monograph Page 1 of 50

2 PRODUCT MONOGRAPH Pr pms-fluconazole Fluconazole Tablets, House Standard 50 mg and 100 mg Antifungal ACTION AND CLINICAL PHARMACOLOGY Fluconazole is a highly selective inhibitor of fungal cytochrome P450 sterol C-14-αdemethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14-α-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. INDICATIONS AND CLINICAL USE Treatment pms-fluconazole (fluconazole) is indicated for the treatment of: 1. Oropharyngeal and esophageal candidiasis. pms-fluconazole is also effective for the treatment of serious systemic candidal infections, including urinary tract infection, peritonitis, and pneumonia. 2. Cryptococcal meningitis. 3. Prevention of the recurrence of cryptococcal meningitis in patients with acquired immunodeficiency syndrome (AIDS). Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly. Prophylaxis pms-fluconazole is also indicated to decrease the incidence of candidiasis in patients undergoing bone marrow transplantation who receive cytotoxic chemotherapy and/or radiation therapy. pms-fluconazole Product Monograph Page 2 of 50

3 CONTRAINDICATIONS pms-fluconazole (fluconazole) is contraindicated in patients who have shown hypersensitivity to fluconazole or to any of its excipients. There is no information regarding cross hypersensitivity between fluconazole and other azole antifungal agents. Caution should be used in prescribing fluconazole to patients with hypersensitivity to other azoles. Co-administration of terfenadine is contraindicated in patients receiving pms-fluconazole at multiple doses of 400 mg or higher based upon results of a multiple dose interaction study. Co-administration of other drugs known to prolong the QT interval and which are metabolised via the enzyme CYP3A4 such as cisapride, astemizole, erythromycin, pimozide and quinidine are contraindicated in patients receiving fluconazole (see PRECAUTIONS Drug Interactions). WARNINGS Fluconazole should be administered with caution to patients with liver dysfunction. Hepatic injury: Fluconazole has been associated with rare cases of serious hepatic toxicity, including fatalities, primarily in patients with serious underlying medical conditions. In cases of fluconazole-associated hepatotoxicity, no obvious relationship to total daily dose, duration of therapy, sex or age of the patient has been observed. Fluconazole hepatotoxicity has usually, but not always, been reversible on discontinuation of therapy. Patients who develop abnormal liver function tests during pms- FLUCONAZOLE therapy should be monitored for the development of more severe hepatic injury. pms-fluconazole should be discontinued if clinical signs and symptoms consistent with liver disease develop that may be attributable to fluconazole. Fluconazole should be administered with caution to patients with renal dysfunction (see DOSAGE and ADMINISTRATION - Impaired Renal Function). Anaphylaxis: In rare cases, anaphylaxis has been reported. Dermatologic: Patients have rarely developed exfoliative skin disorders during treatment with fluconazole. In patients with serious underlying diseases (predominantly AIDS and malignancy), those have rarely resulted in a fatal outcome. Patients who develop rashes during treatment with pms-fluconazole should be monitored closely and the drug discontinued if lesions progress. Use in Pregnancy There are no adequate and well-controlled studies of fluconazole in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in-utero to high dose maternal fluconazole (400- pms-fluconazole Product Monograph Page 3 of 50

4 800 mg/day) during most or all of the first trimester. These reported anomalies are similar to those seen in animal studies. pms-fluconazole (fluconazole) is not recommended in pregnant women unless the potential benefit outweighs the potential risk to mother and fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus (see PRECAUTIONS, Use in Pregnancy). PRECAUTIONS QT Prolongation Some azoles, including fluconazole, have been associated with prolongation of the QT interval on an electrocardiogram. During post-marketing surveillance, there have been very rare cases of QT prolongation and torsade de pointes in patients taking fluconazole. These reports included seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities and concomitant medications that may have been contributory. Fluconazole should be administered with caution to patients with these potentially proarrhythmic conditions (see PRECAUTIONS - Drug Interactions - Drugs prolonging the QTc interval and ADVERSE REACTIONS). CYP2C9, CYP2C19 and CYP3A4 metabolized drugs Fluconazole is a potent CYP2C9 and CYP2C19 inhibitor and a moderate CYP3A4 inhibitor. Fluconazole treated patients who are concomitantly treated with drugs with a narrow therapeutic window metabolised through CYP2C9, CYP2C19 and CYP3A4 should be monitored (see CONTRAINDICATIONS). Use in Pregnancy There are no adequate and well-controlled studies in pregnant women. There have been reports of multiple congenital abnormalities in infants whose mothers were treated with high dose ( mg/day) fluconazole therapy for coccidioidomycosis (an unapproved indication). Exposure to fluconazole began during the first trimester in all cases and continued for three months or longer. pms-fluconazole (fluconazole) is not recommended in pregnant women unless the potential benefit outweighs the potential risk to mother and fetus. Fluconazole was administered orally to pregnant rabbits during organogenesis in two studies: at 5, 10 and 20 mg/kg, and at 5, 25 and 75 mg/kg respectively. Maternal weight gain was impaired at all dose levels, and abortions occurred at 75 mg/kg (approximately 9.4x the maximum recommended human dose); no adverse fetal effects were detected. In several studies in which pregnant rats were treated orally with fluconazole during organogenesis, maternal weight gain was impaired and placental weights were increased at the 25 mg/kg dose. There were no fetal effects at 5 or 10 mg/kg; increases in fetal anatomical variants (supernumerary ribs, renal pelvis dilation) and delays in ossification were observed at 25 and 50 mg/kg and higher doses. At doses ranging from 80 mg/kg to 320 mg/kg (approximately 10-40x the maximum recommended human dose), embryolethality in rats was increased and fetal abnormalities included wavy ribs, cleft palate and abnormal cranio-facial ossification. These effects are pms-fluconazole Product Monograph Page 4 of 50

5 consistent with the inhibition of estrogen synthesis in rats and may be a result of known effects of lowered estrogen on pregnancy, organogenesis and parturition. A few published case reports describe a distinctive and rare pattern of birth defects among infants whose mother received high-dose ( mg/day) fluconazole during most or all of the first trimester of pregnancy. The features seen in these infants include: brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These reported anomalies are similar to those seen in animal studies. pms-fluconazole should not be used in pregnant women unless the potential benefit outweighs the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Use in Women of Child-bearing Potential Since the teratologic effects of fluconazole in humans are unknown, women taking pms- FLUCONAZOLE should consider using adequate contraception (see Use in Pregnancy). There have been reports of multiple congenital abnormalities in infants whose mothers were treated with high dose ( mg/day) fluconazole therapy for coccidioidomycosis (an unapproved indication). Exposure to fluconazole began during the first trimester in all cases and continued for three months or longer. Since there are no adequate studies in pregnant women to assess the potential for fetal risk, pms-fluconazole should not be used in pregnant women unless the potential benefit outweighs the potential risk to the fetus. Use in Nursing Mothers Fluconazole is secreted in human breast milk at concentrations similar to plasma, hence its use in nursing mothers is not recommended. Use in Children The tablets of pms-fluconazole cannot be given to children less than 6 years old. An open-label, randomized, controlled trial has shown fluconazole to be effective in the treatment of oropharyngeal candidiasis in children 6 months to 13 years of age. In a non-comparative study of children with serious systemic fungal infections, fluconazole was effective in the treatment of candidemia (10 of 11 patients cured) and disseminated candidiasis (5 of 6 patients cured or improved). Fluconazole was effective for the suppression of cryptococcal meningitis and/or disseminated cryptococcal infection in a group of 6 children treated in a compassionate study of fluconazole for the treatment of life-threatening or serious mycosis. There is no information regarding the efficacy of fluconazole for primary treatment of cryptococcal meningitis in children. pms-fluconazole Product Monograph Page 5 of 50

6 In addition, the use of fluconazole in children with cryptococcal meningitis, candidal esophagitis or systemic candidal infections is consistent with the approved use of fluconazole in similar indications for adults, and is supported by pharmacokinetic studies in children (see PHARMACOLOGY) establishing dose proportionality between children and adults (see DOSAGE AND ADMINISTRATION). The safety of fluconazole in children has been established in 577 children ages 1 day to 17 years who received doses ranging from 1 to 15 mg/kg/day for 1 to 1616 days (see ADVERSE REACTIONS). Efficacy of fluconazole has not been established in infants less than 6 months of age. A small number of patients (29) ranging in age from 1 day to 6 months have been treated safely with fluconazole. Use in Elderly Fluconazole was well tolerated by patients aged 65 years and over. Fluconazole is primarily cleared by renal excretion as unchanged drug. Because elderly patients are more likely to have decreased renal function, caution should be exercised and dose adjusted based on creatinine clearance. It may be useful to monitor renal function. In a small number of elderly patients with bone marrow transplant (BMT) in which fluconazole was administered prophylactically there was a greater incidence of drug discontinuation due to adverse reactions (4.3%) than in younger patients (1.7%). Effects on Ability to Drive and Use Machines When driving vehicles or operating machines it should be taken into account that occasionally dizziness or seizures may occur. Superinfections Development of resistance to fluconazole has not been studied; however, there have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy. As for other anti-infectives used prophylactically, prudent medical practice dictates that fluconazole be used judiciously in prophylaxis, in view of the theoretical risk of emergence of resistant strains. Drug Interactions Fluconazole is a potent inhibitor of cytochrome P450 (CYP) isoenzyme 2C9, 2C19 and a moderate inhibitor of CYP3A4. In addition to the observed/documented interactions mentioned below, there is a risk of increased plasma concentration of other compounds metabolized by CYP2C9, CYP2C19 and CYP3A4 co-administered with fluconazole. Therefore caution should be exercised when using these combinations and the patients should be carefully monitored. The pms-fluconazole Product Monograph Page 6 of 50

7 enzyme inhibiting effect of fluconazole persists 4-5 days after discontinuation of fluconazole treatment due to the long half-life of fluconazole. Clinically or potentially significant drug interactions between fluconazole and the following agents/classes have been observed: Alfentanil Amitriptyline/Nortriptyline Amphotericin B Azithromycin Benzodiazepines (Short Acting) Carbamazepine Calcium Channel Blockers Celecoxib Cimetidine Coumarin-Type Anticoagulants Cyclosporine Cyclophosphamide Drugs prolonging QTc interval: Astemizole, Cisapride, Terfenadine, Pimozide, Quinidine, Erythromycin Fentanyl Halofantrine HMG-CoA reductase inhibitors Hydrochlorothiazide Losartan Methadone Non-steroidal anti-inflammatory drugs Oral Contraceptives Oral Hypoglycemics Phenytoin Prednisone Rifabutin Rifampin Saquinavir Sirolimus Sulfonylureas Tacrolimus Theophylline Tofacitinib Triazolam Vinca Alkaloids Vitamin A Zidovudine Voriconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibitors) pms-fluconazole Product Monograph Page 7 of 50

8 Alfentanil A study observed a reduction in clearance and distribution volume as well as prolongation of T ½ of alfentanil following concomitant treatment with fluconazole. A possible mechanism of action is fluconazole s inhibition of CYP3A4. Dosage adjustment of alfentanil may be necessary. Amitriptyline, nortriptyline Fluconazole increases the effect of amitriptyline and nortriptyline. 5-nortriptyline and/or S- amitriptyline may be measured at initiation of the combination therapy and after one week. Dosage of amitriptyline/nortriptyline should be adjusted, if necessary. Amphotericin B Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with Aspergillus fumigates. The clinical significance of results obtained in these studies is unknown. Azithromycin An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 1200 mg oral dose of azithromycin on the pharmacokinetics of a single 800 mg oral dose of fluconazole as well as the effects of fluconazole on the pharmacokinetics of azithromycin. There was no significant pharmacokinetic interaction between fluconazole and azithromycin (see DRUG INTERACTION STUDIES). Benzodiazepines (Short Acting) Following oral or intravenous administration of midazolam, fluconazole resulted in substantial increases in midazolam concentrations and psychomotor effects. This effect on midazolam appears to be more pronounced following oral administration of fluconazole than with fluconazole administered intravenously. If short-acting benzodiazepines, which are metabolized by the cytochrome P450 system, are concomitantly administered with fluconazole, consideration should be given to decreasing the benzodiazepine dosage, and the patients should be appropriately monitored. (see DRUG INTERACTION STUDIES). Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C max by 2032%, and increases t½ by 25-50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary. Carbamazepine Fluconazole inhibits the metabolism of carbamazepine and an increase in serum carbamazepine of 30% has been observed. There is a risk of developing carbamazepine toxicity. Dosage adjustment of carbamazepine may be necessary depending on concentration measurements/effect. pms-fluconazole Product Monograph Page 8 of 50

9 Calcium Channel Blockers Certain calcium channel antagonists (nifedipine, isradipine, amlodipine, verapamil and felodipine) are metabolized by CYP3A4. Fluconazole has the potential to increase the systemic exposure of the calcium channel antagonists. Frequent monitoring for adverse events is recommended. Celecoxib During concomitant treatment with fluconazole (200 mg daily) and celecoxib (200 mg) the celecoxib C max and AUC increased by 68% and 134%, respectively. Half of the celecoxib dose may be necessary when combined with fluconazole. Caution should be exercised and patients should be monitored for increased toxicity of celecoxib as well as careful monitoring of celecoxib associated adverse events. Cimetidine Absorption of orally administered fluconazole does not appear to be affected by gastric ph. Fluconazole 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC (area under the plasma concentration-time curve) and C max. There was a mean ± SD decrease in fluconazole AUC of 13% ± 11% (range -3.4 to -31%) and C max decreased 19% ± 14% (range: -5 to -40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a 4-hour period (from 1 hour before to 3 hours after a single oral dose of fluconazole 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers (see DRUG INTERACTION STUDIES). Coumarin-Type Anticoagulants Prothrombin time may be increased in patients receiving concomitant fluconazole and coumarin-type anticoagulants. In post-marketing experience, as with some azole antifungals, bleeding events (bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena) have been reported in association with increases in prothrombin time in patients receiving fluconazole concurrently with warfarin. Dose adjustments of warfarin may be necessary. Careful monitoring of prothrombin time in patients receiving pms-fluconazole and coumarin-type anticoagulants is recommended (see DRUG INTERACTION STUDIES). Cyclosporine Fluconazole may significantly increase the concentration and AUC of cyclosporine levels in renal transplant patients with or without renal impairment. Careful monitoring of cyclosporine concentrations and serum creatinine is recommended in patients receiving pms- FLUCONAZOLE and cyclosporine. This combination may be used by reducing the dosage of cyclosporine depending on cyclosporine concentration (see DRUG INTERACTION STUDIES). Cyclophosphamide Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine. The combination may be used while taking increased pms-fluconazole Product Monograph Page 9 of 50

10 consideration to the risk of increased serum bilirubin and serum creatinine. Caution should be exercised and patients should be monitored for increased toxicity of cyclophosphamide. Tofacitinib Exposure is increased when tofacitinib is co-administered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Drugs prolonging the QTc interval The use of fluconazole in patients concurrently taking drugs metabolized by the Cytochrome P450 system may be associated with elevations in the serum levels of these drugs. In the absence of definitive information caution should be used when co-administering pms- FLUCONAZOLE and such agents (see PRECAUTIONS - QT Prolongation). Patients should be carefully monitored. Concomitant use of the following other medicinal products is contraindicated: Astemizole: Concomitant administration of fluconazole with astemizole may decrease the clearance of astemizole. Resulting increased plasma concentrations of astemizole can lead to QT prolongation and rare occurrences of torsade de pointes. Co-administration of fluconazole and astemizole is contraindicated (see CONTRAINDICATIONS). Cisapride: There have been reports of cardiac events including torsade de pointes in patients to whom fluconazole and cisapride were co-administered. A controlled study found that concomitant fluconazole 200 mg once daily and cisapride 20 mg four times a day yielded a significant increase in cisapride plasma levels and prolongation of QTc interval. Coadministration of cisapride is contraindicated in patients receiving pms-fluconazole (see CONTRAINDICATIONS and DRUG INTERACTION STUDIES). Terfenadine: Because of the occurrence of serious cardiac dysrhythmias secondary to prolongation of the QTc interval in patients receiving azole antifungals in conjunction with terfenadine, interaction studies have been performed. In one study, 6 healthy volunteers received terfenadine 60 mg BID for 15 days. One study at 200 mg daily dose of fluconazole failed to demonstrate a prolongation of QTc interval. However, another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. Therefore the combined use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see CONTRAINDICATIONS and DRUG INTERACTION STUDIES). Patients should be carefully monitored if they are being concurrently prescribed pms- FLUCONAZOLE at multiple doses lower than 400 mg/day with terfenadine. Pimozide: Although not studied in vitro or in vivo, concomitant administration of fluconazole with pimozide may result in inhibition of pimozide metabolism. Increased pimozide plasma concentrations can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of fluconazole and pimozide is contraindicated (see PRECAUTIONS). pms-fluconazole Product Monograph Page 10 of 50

11 Quinidine: Although not studied in vitro or in vivo, concomitant administration of fluconazole with quinidine may result in inhibition of quinidine metabolism. Use of quinidine has been associated with QT prolongation and rare occurrences of torsade de pointes. Co-administration of fluconazole and quinidine is contraindicated (see CONTRAINDICATIONS). Erythromycin: Concomitant use of fluconazole and erythromycin has the potential to increase the risk of cardiotoxicity (prolonged QT interval, torsade de pointes) and consequently sudden heart death. Co-administration of fluconazole and erythromycin is contraindicated (see CONTRAINDICATIONS). In a large cohort of patients, the multivariate adjusted rate of sudden death from cardiac causes was five times as high among those who concurrently used CYP3A inhibitors and erythromycin compared with those who had used neither CYP3A inhibitors nor any of the study antibiotic medications. Fentanyl One fatal case of possible fentanyl fluconazole interaction was reported. The author judged that the patient died from fentanyl intoxication. Furthermore, in a randomized crossover study with twelve healthy volunteers it was shown that fluconazole delayed the elimination of fentanyl significantly. Elevated fentanyl concentration may lead to respiratory depression. Patient should be monitored for serious adverse effects such as respiratory depression. Halofantrine Fluconazole can increase halofantrine plasma concentration due to an inhibitory effect on CYP3A4. Caution should be exercised and patients should be monitored for increased toxicity of halofantrine. HMG-CoA reductase inhibitors The risk of myopathy and rhabdomyolysis increases when fluconazole is co-administered with HMG-CoA reductase inhibitors metabolised through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin. If concomitant therapy is necessary, the patient should be observed for symptoms of myopathy and rhabdomyolysis and creatine kinase should be monitored. HMG-CoA reductase inhibitors should be discontinued if a marked increase in creatine kinase is observed or myopathy/rhabdomyolysis is diagnosed or suspected. Hydrochlorothiazide In a pharmacokinetic interaction study, co-administration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentration of fluconazole by 40%. An effect of this magnitude should not necessitate a change in the fluconazole dose regimen in subjects received concomitant diuretics (see DRUG INTERACTION STUDIES). Losartan Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin II-receptor antagonism which occurs during treatment with losartan. Patients should have their blood pressure monitored continuously. pms-fluconazole Product Monograph Page 11 of 50

12 Methadone Fluconazole may enhance the serum concentration of methadone. Dosage adjustment of methadone may be necessary. Non-steroidal anti-inflammatory drugs The C max and AUC of flurbiprofen were increased by 23% and 81%, respectively, when coadministered with fluconazole compared to administration of flurbiprofen alone. Similarly, the C max and AUC of the pharmacologically active isomer [S-(+)-ibuprofen] were increased by 15% and 82%, respectively, when fluconazole was co-administered with racemic ibuprofen (400 mg) compared to administration of racemic ibuprofen alone. Although not specifically studied, fluconazole has the potential to increase the systemic exposure of other NSAIDs that are metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed. Oral Contraceptives Two pharmacokinetic studies with a combined oral contraceptive have been performed using multiple doses of fluconazole. There were no relevant effects on hormone level in the 50 mg fluconazole study, while at 200 mg daily, the AUCs of ethinyl estradiol and levonorgestrel were increased 40% to 24%, respectively. Thus, multiple dose use of fluconazole at these doses is unlikely to have an effect on efficacy of the combined oral contraceptive (see DRUG INTERACTION STUDIES). Oral Hypoglycemics Clinically significant hypoglycemia may be precipitated by the use of fluconazole with oral hypoglycemic agents; one fatality has been reported from hypoglycemia in association with combined fluconazole and glyburide use. Fluconazole reduces the metabolism of tolbutamide, glyburide, and glipizide and increases the plasma concentration of these agents. When pms- FLUCONAZOLE is used concomitantly with these or other sulfonylurea oral hypoglycemic agents, blood glucose concentrations should be carefully monitored and the dose of the sulfonylurea should be adjusted as necessary (see DRUG INTERACTION STUDIES). Phenytoin Fluconazole increases the plasma concentrations of phenytoin. Careful monitoring of phenytoin concentrations in patients receiving pms-fluconazole and phenytoin is recommended (see DRUG INTERACTION STUDIES). Prednisone There was a case report that a liver-transplanted patient treated with prednisone developed acute adrenal cortex insufficiency when a three month therapy with fluconazole was discontinued. The discontinuation of fluconazole presumably caused an enhanced CYP3A4 activity which led to increased metabolism of prednisone. Patients on long-term treatment with fluconazole and prednisone should be carefully monitored for adrenal cortex insufficiency when pms- FLUCONAZOLE is discontinued. pms-fluconazole Product Monograph Page 12 of 50

13 Rifabutin There have been reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin up to 80%. There have been reports of uveitis in patients to whom fluconazole and rifabutin were coadministered. Patients receiving rifabutin and pms-fluconazole concomitantly should be carefully monitored (see DRUG INTERACTION STUDIES). Rifampin Rifampin enhances the metabolism of concurrently administered fluconazole. Depending on clinical circumstances, consideration should be given to increasing the dose of pms- FLUCONAZOLE when it is administered with rifampin (see DRUG INTERACTION STUDIES). Saquinavir Fluconazole increases the AUC of saquinavir by approximately 50%, C max by approximately 55% and decreases clearance of saquinavir by approximately 50% due to inhibition of saquinavir s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary. Caution should be exercised and patients should be monitored for increased toxicity of saquinavir. Sirolimus Fluconazole increases plasma concentrations of sirolimus presumably by inhibiting the metabolism of sirolimus via CYP3A4 and P-glycoprotein. This combination may be used with a dosage adjustment of sirolimus depending on the effect/concentration measurements. Caution should be exercised and patients should be monitored for increased toxicity of sirolimus. Sulfonylureas Fluconazole has been shown to prolong the serum half-life of concomitantly administered oral sulfonylureas (e.g., chlorpropamide, glibenclamide, glipizide, tolbutamide) in healthy volunteers. Frequent monitoring of blood glucose and appropriate reduction of sulfonylurea dosage is recommended during co-administration. Tacrolimus Fluconazole significantly increases the serum concentrations of orally administered tacrolimus up to 5 times due to inhibition of tacrolimus metabolism through CYP3A4. Increased levels of tacrolimus have been associated with nephrotoxicity. Dosage adjustment of tacrolimus should be made depending on tacrolimus concentration. Patients receiving tacrolimus and pms- FLUCONAZOLE concomitantly should be carefully monitored for tacrolimus associated adverse effects, especially nephrotoxicity (see DRUG INTERACTION STUDIES). Theophylline Patients who are receiving high doses theophylline or who are otherwise at increased risk for theophylline toxicity should be observed for signs of theophylline toxicity while receiving pms- FLUCONAZOLE, and therapy modified appropriately if signs of toxicity develop. Fluconazole increases the serum concentrations of theophylline. Careful monitoring of serum theophylline pms-fluconazole Product Monograph Page 13 of 50

14 concentrations in patients receiving pms-fluconazole and theophylline is recommended (see DRUG INTERACTION STUDIES). Triazolam Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C max with 20-32% and increases t½ by % due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary. Caution should be exercised and patients should be monitored for increased toxicity of triazolam. Vinca Alkaloids Although not studied, fluconazole may increase the plasma levels of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity, which is possibly due to an inhibitory effect on CYP3A4. Caution should be exercised and patients should be monitored for increased toxicity of vinca alkaloids (e.g., vincristine and vinblastine). Vitamin A Based on a case-report in one patient receiving combination therapy with all-trans-retinoid acid (an acid form of vitamin A) and fluconazole, CNS related undesirable effects have developed in the form of pseudotumour cerebri, which disappeared after discontinuation of fluconazole treatment. This combination may be used but the incidence of CNS related undesirable effects should be borne in mind. Zidovudine Fluconazole increases C max and AUC of zidovudine by 84% and 74%, respectively, due to an approx. 45% decrease in oral zidovudine clearance. The half-life of zidovudine was likewise prolonged by approximately 128% following combination therapy with fluconazole. Patients receiving this combination should be monitored for the development of zidovudine-related adverse reactions. Dosage reduction of zidovudine may be considered (see DRUG INTERACTION STUDIES). Voriconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitors) Avoid concomitant administration of voriconazole and fluconazole at any dose. Monitor for adverse events and toxicity related to voriconazole; especially, if voriconazole is started within 24 h after the last dose of fluconazole (see DRUG INTERACTION STUDIES). Interaction studies with other medications have not been conducted, but such interactions may occur. Drug/Laboratory Test Interactions: None known. ADVERSE REACTIONS In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities (see pms-fluconazole Product Monograph Page 14 of 50

15 WARNINGS and PRECAUTIONS) have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain. In Patients Receiving a Single Dose for Vaginal Candidiasis: During comparative clinical studies conducted in the United States, 448 patients with vaginal candidiasis were treated with fluconazole, 150 mg single dose. The overall incidence of side effects possibly related to fluconazole was 26%. In 422 patients receiving active comparative agents, the incidence was 16%. The most common treatment-related adverse events reported in the patients who received 150 mg single dose fluconazole for vaginitis were headache (13%), nausea (7%), and abdominal pain (6%). Other side effects reported with an incidence equal to or greater than 1% included diarrhea (3%), dyspepsia (1%), dizziness (1%), and taste perversion (1%). Most of the reported side effects were mild to moderate in severity. Rarely, angioedema and anaphylactic reaction have been reported in marketing experience. ADULTS Sixteen percent of over 4000 patients treated with fluconazole in clinical trials of 7 days or more experienced adverse events. Treatment was discontinued in 1.5% of patients due to adverse clinical events and in 1.3% of patients due to laboratory test abnormalities. Adverse clinical events were reported more frequently in HIV infected patients (21%) than in non-hiv infected patients (13%). However, the patterns of adverse events in HIV infected and non-hiv infected patients were similar. The proportions of patients discontinuing therapy due to clinical adverse events were similar in the two groups (1.5%). The two most serious adverse clinical events noted during clinical trials with fluconazole were: 1. Exfoliative skin disorders 2. Hepatic necrosis Because most of these patients had serious underlying disease (predominantly AIDS or malignancy) and were receiving multiple concomitant medications, including many known to be hepatotoxic or associated with exfoliative skin disorders, the causal association of these reactions with fluconazole is uncertain. Two cases of hepatic necrosis and one exfoliative skin disorder (Stevens-Johnson syndrome) were associated with a fatal outcome (see WARNINGS). The following treatment-related clinical adverse events occurred at an incidence of 1% or greater in 4,048 patients receiving fluconazole for 7 or more days in clinical trials: Central and Peripheral Nervous System: headache (1.9%) Dermatologic: skin rash (1.8%) Gastrointestinal: abdominal pain (1.7%), diarrhea (1.5%), nausea (3.7%) and vomiting (1.7%). Hepato-biliary disorders: alanine aminotransferase increased, asparate aminotransferase increased, blood alkaline phosphatase increased. pms-fluconazole Product Monograph Page 15 of 50

16 Other treatment-related clinical adverse events which occurred less commonly (0.2 to < 1%) are presented by organ system below: Skin and Appendages: pruritus, urticaria, drug eruption. Musculoskeletal: myalgia. Central and Peripheral Nervous System: convulsions, dizziness, paresthesia, tremor, vertigo, seizures. Autonomic Nervous System: dry mouth, increased sweating. Psychiatric: insomnia, somnolence. Gastrointestinal: anorexia, constipation, dyspepsia, flatulence. Liver and Biliary System: cholestasis, bilirubin increased, jaundice. Special Senses: taste perversion. Hematopoietic: anemia. General: fatigue, malaise, asthenia, fever. Immunologic: In rare cases, anaphylaxis has been reported. Hepatobiliary: In combined clinical trials and marketing experience, there have been rare cases of serious hepatic reactions during treatment with fluconazole (see WARNINGS). The spectrum of these hepatic reactions has ranged from mild transient elevations in transaminases to clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities. Instances of fatal hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly AIDS or malignancy) and often while taking multiple concomitant medications. Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. In each of these cases, liver function returned to baseline on discontinuation of fluconazole. In two comparative trials evaluating the efficacy of fluconazole for the suppression of relapse of cryptococcal meningitis, a statistically significant increase was observed in median AST (SGOT) levels from a baseline value of 30 IU/L to 41 IU/L in one trial and 34 IU/L to 66 IU/L in the other. The overall rate of serum transaminase elevations of more than 8 times the upper limit of normal was approximately 1% in fluconazole-treated patients in clinical trials. These elevations occurred in patients with severe underlying disease, predominantly AIDS or malignancies, most of whom were receiving multiple concomitant medications, including many known to be hepatotoxic. The incidence of abnormally elevated serum transaminases was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral sulfonylurea hypoglycemic agents. Post-Marketing Experience In addition, the following adverse events have occurred under conditions where a causal association is uncertain (e.g., open trials, during post-marketing experience): Cardiovascular: QT prolongation, torsade de pointes (see PRECAUTIONS - QT Prolongation). Body As A Whole: Asthenia, fatigue, fever, malaise and urticaria. Central Nervous System: Seizures, dizziness. pms-fluconazole Product Monograph Page 16 of 50

17 Dermatologic: Alopecia, acute generalized exanthematous-pustulosis, face edema, exfoliative skin disorders including Stevens-Johnson Syndrome and toxic epidermal necrolysis, dermatitis exfoliative (see WARNINGS), drug eruption, increased sweating. Gastrointestinal: Cholestasis, dry mouth, hepatocellular damage, dyspepsia, vomiting. Hematopoietic and Lymphatic: Leukopenia, including neutropenia and agranulocytosis, thrombocytopenia. Immunologic: In rare cases, anaphylaxis including angioedema, face edema, and pruritus. Liver/Biliary: Hepatic toxicity, including rare cases of fatalities, hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular damage. Metabolic: Hypercholesterolemia, hypertriglyceridemia, hypokalemia. Musculoskeletal: Myalgia. Nervous System: Tremor, insomnia, paresthesia, somnolence, vertigo. Other Senses: Taste perversion. Laboratory Test Abnormalities Liver Function Clinically significant increases were observed in the following proportions of patients: AST 1%, ALT 1.2%, alkaline phosphatase 1.2%, total bilirubin 0.3%. The incidence of elevated serum aminotransferases was independent of age or route (p.o. or i.v.) of administration but was greater in patients taking fluconazole concomitantly with one or more of the following medications: rifampin, phenytoin, isoniazid, valproic acid, or oral hypoglycemic agents. Clinically significant increases also were more frequent in patients who: 1) had AST or ALT elevations greater than three times the upper limit of normal (> 3xULN) at the time of entering the study (baseline), 2) had a diagnosis of hepatitis at any time during the study and, 3) were identified as alcohol abusers. The overall rate of serum aminotransferase elevations of more than 8 times the upper limit of normal was approximately 1% in patients treated with fluconazole during clinical trials (see Table I). TABLE I LAB PARAMETER #* OF PATIENTS % ABNORMAL # OF PATIENTS % ABNORMAL AST ALT BASELINE > 3xULN BASELINE < 3xULN HEPATITIS PATIENTS NON-HEPATITIS PATIENTS AST ALT AST ALT ALCOHOL ABUSE NON-ALCOHOL ABUSE pms-fluconazole Product Monograph Page 17 of 50

18 LAB PARAMETER AST ALT #* OF PATIENTS % ABNORMAL RECEIVED IV FLUCONAZOLE # OF PATIENTS % ABNORMAL NEVER RECEIVED IV FLUCONAZOLE AST ALT > 65 YEARS OLD < 65 YEARS OLD * NOTE: Only patients who had measurements at baseline and during therapy were included. Renal Function Clinically significant increases were observed in the following proportions of patients: blood urea nitrogen (0.4%) and creatinine (0.3%). Hematological Function Clinically meaningful deviations from baseline in hematologic values which were possibly related to fluconazole were observed in the following proportions of patients: hemoglobin (0.5%), white blood cell count (0.5%), and total platelet count (0.6%). CHILDREN The tablets of pms-fluconazole cannot be given to children less than 6 years old. The pattern and incidence of adverse events and laboratory abnormalities recorded during pediatric clinical trials are comparable to those seen in adults. In Phase II/III clinical trials conducted in the United States and in Europe, 577 pediatric patients, ages 1 day to 17 years were treated with fluconazole at doses ranging up to 15 mg/kg/day for up to 1616 days. Thirteen percent of children experienced treatment-related adverse events. The most commonly reported events were vomiting (5.4%), abdominal pain (2.8%), nausea (2.3%), and diarrhea (2.1%). Treatment was discontinued in 2.6% of patients due to adverse clinical events and in 1.0% of patients due to laboratory test abnormalities. The majority of treatment- related laboratory abnormalities were elevations of transaminases or alkaline phosphatase. Percentage of Patients with Treatment-Related Side Effects Fluconazole Comparative Agent (N=577) (N=451) With any side effect Vomiting Abdominal pain Nausea Diarrhea pms-fluconazole Product Monograph Page 18 of 50

19 SYMPTOMS AND TREATMENT OF OVERDOSAGE Activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended. Symptoms: There have been reports of overdosage with fluconazole accompanied by hallucination and paranoid behaviour. Treatment: In the event of overdose, symptomatic treatment (with supportive measures and gastric lavage if necessary) may be adequate. Fluconazole is largely excreted in urine. A three hour hemodialysis session decreases plasma levels by approximately 50%. Mice and rats receiving very high doses of fluconazole, whether orally or intravenously, displayed a variety of nonspecific, agonal signs such as decreased activity, ataxia, shallow respiration, ptosis, lacrimation, salivation, urinary incontinence and cyanosis. Death was sometimes preceded by clonic convulsions. For management of a suspected drug overdose, contact your regional Poison Control Centre immediately DOSAGE AND ADMINISTRATION pms-fluconazole (fluconazole) is well absorbed and excreted predominantly unchanged in urine following oral administration in humans. The oral bioavailability is essentially complete (greater than 90%), and is independent of dose. Peak plasma concentrations after oral administration are attained rapidly, usually within 2 hours of dosing. The terminal plasma elimination half-life is approximately 30 hours (range hours). The daily dose of pms-fluconazole and the route of administration should be based on the infecting organism, the patient s condition and the response to therapy. Treatment should be continued until clinical parameters and laboratory tests indicate that an active fungal infection has been cured or has subsided. An inadequate period of treatment may lead to recurrence of active infection. Patients with AIDS and cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require maintenance therapy to prevent relapse. RECOMMENDED DOSAGES IN ADULTS AND CHILDREN (also see PHARMACOLOGY) TREATMENT Loading Dose The tablets of pms-fluconazole cannot be given to children less than 6 years old. pms-fluconazole Product Monograph Page 19 of 50

20 Administration of a loading dose on the first day of treatment, consisting of twice the usual daily dose, results in plasma concentrations close to steady state by the second day. Patients with acute infections should be given a loading dose equal to twice the daily dose, not to exceed a maximum single dose of 400 mg in adults or 12 mg/kg in children, on the first day of treatment. Dosage Equivalency Scheme Pediatric Patients Adults 3 mg/kg 100 mg 6 mg/kg 200 mg 12 mg/kg* 400 mg * Some older children may have clearances similar to that of adults. Absolute doses exceeding 600 mg/day are not recommended. Recommended Treatment Guidelines Indication Adults Children Oropharyngeal Candidiasis Esophageal Candidiasis Systemic Candidiasis (Candidemia and Disseminated Candidal Infections) Cryptococcal Meningitis Prevention of Recurrence of Cryptococcal Meningitis in Patients with AIDS 100 mg once daily for at least 2 weeks to decrease the likelihood of relapse. 100 mg to 200 mg once daily for a minimum of 3 weeks, and for at least 2 weeks following resolution of symptoms. 200 mg to 400 mg once daily for a minimum of 4 weeks, and for at least 2 weeks following resolution of symptoms. 200 mg to 400 mg once daily. The duration of therapy for cryptococcal meningitis is unknown, it is recommended that the initial therapy should last a minimum of 10 weeks. 3 mg/kg once daily for at least 2 weeks to decrease the likelihood of relapse. 3 mg/kg to 6 mg/kg once daily for a minimum of 3 weeks, and for at least 2 weeks following resolution of symptoms. 6 mg/kg to 12 mg/kg per day have been used in an open, non-comparative study of a small number of patients. 6 mg/kg to 12 mg/kg once daily. The recommended duration for initial therapy is weeks after the cerebrospinal fluid becomes culture-negative. 200 mg once daily. 6 mg/kg once daily. PREMATURE NEONATES The tablets of pms-fluconazole cannot be given to children less than 6 years old. pms-fluconazole Product Monograph Page 20 of 50

21 Experience with fluconazole in neonates is limited to pharmacokinetic studies in premature newborns (see PHARMACOLOGY). Based upon the prolonged half-life seen in premature newborns (gestation age 26 to 29 weeks), these children, in the first two weeks of life, should receive the same dosage (mg/kg) as in older children, but administered every 72 hours. After the first two weeks, these children should be dosed once daily. NEONATES No information regarding fluconazole pharmacokinetics in full-term newborns is available. PROPHYLAXIS IN ADULT PATIENTS The recommended pms-fluconazole daily dosage for the prevention of candidiasis in adult patients undergoing bone marrow transplantation is 400 mg once daily. Patients who are anticipated to have severe granulocytopenia (less than 500 neutrophils per mm 3 ) should start pms-fluconazole prophylaxis several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 1000 cells per mm 3. DOSAGE IN PATIENTS WITH IMPAIRED RENAL FUNCTION Adults Fluconazole is cleared primarily by renal excretion as unchanged drug. In patients with impaired renal function, an initial loading dose of 50 to 400 mg should be given (for children, see below). After the loading dose, the daily dose (according to indication) should be based on the following table: Creatinine Clearance (ml/min) > (no dialysis) (no dialysis) Regular hemodialysis Creatinine Clearance (ml/sec) > (no dialysis) (no dialysis) Regular hemodialysis Percent Recommended Dose 100% 50% 25% 100% after each dialysis Patients on regular dialysis should receive 100% of the recommended dose after each dialysis; on non-dialysis days, patients should receive a reduced dose according to their creatinine clearance. When serum creatinine is the only measure of renal function available, the following formula (based on sex, weight, and age of the patient) should be used to estimate the creatinine clearance. Creatinine Clearance Calculations Males: ml/min Weight (kg) x (140-age) ml/sec Weight (kg) x (140-age) 72 x serum creatinine (mg/100ml) 50 x serum creatinine (mcmol/l) Females: 0.85 x above value 0.85 x above value pms-fluconazole Product Monograph Page 21 of 50

22 Children Although the pharmacokinetics of fluconazole have not been studied in children with renal insufficiency, dosage reduction in children with renal insufficiency should parallel that recommended for adults. The following formula may be used to estimate creatinine clearance in children: K x linear length or height (cm) serum creatinine (mg/100 ml) (Where K=0.55 for children older than 1 year and 0.45 for infants.) pms-fluconazole Product Monograph Page 22 of 50